PurposeSorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) –negative breast cancer.Patients and MethodsPatients were randomly assigned to first- or second-line capecitabine 1,000 mg/m2orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS).ResultsIn total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand- foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively).ConclusionAddition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

Introduction: Access to targeted therapies for lung cancer depends on the accurate identification of patients' biomarkers through molecular testing. The International Association for the Study of Lung Cancer (IASLC) conducted an international survey to evaluate perceptions on current practice and barriers to implementation of molecular testing. Methods: We distributed the survey to IASLC members and other health care professionals around the world. The survey included a seven-question introduction for all respondents, who then answered according to one of three tracks: (1) requesting tests and treating patients, (2) performing and interpreting assays, or (3) tissue acquisition. Barriers to implementing molecular testing were provided in free-response fields. The chi-square test was used for regional comparisons. Results: A total of 2537 respondents from 102 countries participated. Most respondents who test and treat patients believe that less than 50% of patients with lung cancer in their country receive molecular testing, but reported higher rates within their own practice. Although many results varied by region, the five most frequent barriers cited in all regions were cost, quality and standards, access, awareness, and turnaround time. Many respondents expressed dissatisfaction with the current state of molecular testing for lung cancer, including 41% of those performing and interpreting assays. Issues identified included trouble understanding results (37%) and the quality of the samples (23% reported >10% rejection rate). Despite concerns regarding the quality of testing, 47% in the performing and interpreting track stated there is no policy or strategy to improve quality in their country. In addition, 33% of respondents who request tests and treat patients were unaware of the most recent College of American Pathologists, IASLC, and Association for Molecular Pathology guidelines for molecular testing. Conclusions: Adoption of molecular testing for lung cancer is relatively low across the world. Barriers include cost, access, quality, turnaround time, and lack of awareness.

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Nota: Estas diretrizes se prestam a informar e não a substituir o julgamento clínico do médico que, em última análise, deve determinar o tratamento apropriado para seus pacientes.

Chemokines and their receptors are broadly expressed in different tissues and are involved in diverse biologic processes. Gene inactivation studies have shown that both stromal cell derived factor-1 (SDF-1) and chemokine receptor 4 (CXCR4) are essential for B lymphopoiesis. However, it is not yet clear by which mechanisms B lymphopoiesis is affected. In the present study, we have examined CXCR4 expression and function on primary B cells representing sequential stages of development (eg, pro-B, pre-B, immature, and mature B cells) in fetal and adult bone marrow. The expression of CXCR4 was observed to be sinusoidal. Expression was highest on pre-B cells, decreased as cells developed into immature B cells, and then increased again upon transition to the mature B-cell stage. The corresponding ligand SDF-1 was shown to trigger vigorous cell signaling and migration responses, which are restricted to early lineage B cells. The responsiveness to SDF-1 was markedly decreased for immature and mature B cells despite relatively high levels of CXCR4 expression. Thus, the diminished responsiveness to SDF-1 by more mature B cells was determined to be disproportionate to the level of CXCR4 expression. These findings raise the possibility that CXCR4 function is differentially controlled during B lymphopoiesis and may be relevant to the compartmentalization of B-cell precursors in the bone marrow.